• Introduction
• Stage I: Acute HIV Syndrome
• Clinical Latency
• Early Disease Presentation
• Neurological Manifestations
  • Aseptic Meningitis
  • HIV Encephalopathy
  • Spinal Cord Manifestions
  • Peripheral Neuropathies
  • Myopathy
• Attribution

  Opportunistic Infections

  • Introduction
  • Protozoal Infections
    • Pneumocystis carinii Treatment
    • Pneumocystis carinii Prophylaxis
    • Toxoplasmosis
      • Treatment
      • Prophylaxis
  • Protozoal Diarrhea
  • Bacterial Infections
    • Introduction
    • Mycobacterial Infection
    • Tuberculosis
      • Treatment
  • Fungal Infections
    • Candidiasis
      • Treatment
    • Cryptococcosis
      • Treatment
    • Histoplasmosis
      • Treatment

Opportunistic Viral Infections

• Herpes Virus Infection
• Cytomegalovirus Infection
  • Treatment
• Varicella-Zoster Infection
• Epstein-Barr Virus
• Other Human Herpes Viral Infections

Neoplastic Disease

• Introduction
• Kaposi Sarcoma
  • Treatment
• Lymphoma
  • Treatment
• Intraepithelial Dysplasis of the Cervix or Anus

•  CNS manifestation of HIV-infection: significant morbidity in a high percentage of HIV patients.
• Primary: direct effect of HIV infection.
• Secondary: sequelae of opportunistic infections.
  •  toxoplasmosis
  •  cryptococcus
  •  cytomegalovirus (CMV)
  •  HTLV-1
  •  Mycobacterium tuberculosis
  •  progressive multifocal leukoencephalopathy
  •  syphilis
  •  primary CNS lymphoma
• Categories of neurological effects: inflammatory, demyelinating, degenerative
• AIDS-defining neurological disorder: AIDS dementia (HIV encephalopathy)
• CNS pathology:
  •  direct effect on glial cells and macrophages
  •  secondary effects due to neurotoxin release and possibly release of cytokines such as TGF-beta, IL-6, TNF alpha, IL-1 beta.
• Based on abnormal CSF findings, most (> 90%) of HIV patients have some CMS involvement.
• CNS HIV infection does not necessarily result in clinically-relevant neurologic symptoms.

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• Not seen in the very late stages of HIV disease
• In acute primary infection,symptoms: headache, photophobia, occasionally encephalitis
• CNS findings: elevated protein, lymphocytic pleocytosis.
• Cranial nerve involvement: usually VII (and occasionally V and/or VIII).
• Most likely an immune-mediated disease.

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• Also called HIV-associated dementia or AIDS dementia complex.
• Generally occurs late in HIV infection.
• Major feature is decline in cognitive abilities -- symptoms that, at least initially, could suggest situational depression or fatigue
• Dementia may be accompanied by some motor and behavioral abnormalities.
  • Motor dysfunction: unsteady gait, tremor, poor balance; Advanced manifestations include incontinence (bowel and/or bladder).
  • Behavioral difficulties: apathy, agitation, mild mania, possible progression in some cases to a vegetative state.
• HIV encephalopathy: rarely the initial AIDS-defining presentations (3%).
• Ultimately significant HIV dementia develops and about 25% of all patients.
• Autopsy analysis indicates > 80% of HIV patients have histologic evidence of CNS disease
• Basis of HIV encephalopathy: probably due to direct viral effects.
  • HIV identified in patient's brains
  • Main CNS viral reservoirs: macrophages, micro-glial cells and multinucleated giant cells.
• Primary involvement is in subcortical regions, similar to the involvement profile seen in Parkinson's disease and Huntington's disease, and dissimilar to that seen in Alzheimer's disease.
•  No specific treatment at present for HIV encephalopathy;some reports have indicated that antiretroviral drugs may be beneficial.
  • improvement in neuropsychiatric tests(Mini-Mental Status Examination) associated with either zidovudine (Retrovir, AZT, azidothymidine) or didanosine (Videx, ddI).

•  Patients with HIV encephalopathy: increased sensitivity to adverse effects of antipsychotic drugs -- such patients must be managed carefully, if antipsychotic medication is to be employed for symptomatic treatment.

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•  Myelopathy occurs at about one-fifth of AIDS patients.
•  Myelopathy may be part of a generalized HIV encephalopathy.
• Three main types of spinal cord disease have been reported in HIV patients.
  • vacuolar encephalopathy (similar to subacute combined cord degeneration, seen also in pernicious anemia.
    • subacute onset
    • gait disturbances [ataxia, spasticity]
  • Dorsal column disease: pure sensory ataxia
  • Sensory:parathesias, dysethesias of the lower extremities
•  Most spinal cord syndromes do not respond to antiviral drug therapy, in contrast to improvement in cognitive function seen following antiviral treatment in patients with HIV encephalopathy.
• Polyradiculopathy due to cytomegalovirus (CMV), observed late in HIV infection; associated with lower extremity and sacral parathesia, areflexia, ascending sensory loss, urinary retention, difficulty in walking -- condition responds rapidly to treatment with ganciclovir or foscarnet .

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•  Common in HIV infection
• Early syndrome: inflammatory demyelinating polyneuropathy or [similar to Guillain-Barre syndrome]
• Characterized by: progressive weakness, areflexia, some sensory change
• Often self-limiting, however, severe cases may require plasma exchange, IV immunoglobulin, systemic glucocorticoids.
•  Note that glucocorticoid-mediated immunosuppression is not desirable; therefore, glucocorticoid use should be limited to severe cases.
• Mononeuritis multiplex: a necrotizing arteritis of peripheral nerves, also seen in HIV patients.
•  Most common peripheral neuropathy in HIV patients: a distal sensory polyneuropathy [in advanced HIV disease]
  • about two-thirds of AIDS patients have peripheral nerve disease as determined by electrophysiology.
  • Distal sensory polyneuropathy probably due to HIV-mediated axonal degeneration.
  • Clinical presentation: symmetrical bilateral painful burning sensation in feet and lower extremities.
  •  Antiviral drugs are not effective in treating this condition and may in fact be responsible for it in some circumstances.
    • --dideoxynucleoside-associated peripheral neuropathy --a complication of didanosine (Videx, ddI), zalcitabine (Hivid, ddc) or stavudine (Zerit, d4T). The drug-induced condition usually resolves following cessation of treatment.
    • If sensory polyneuropathy does not resolve after discontinuing dideoxynucleoside antivirals, treatment is symptomatic, utilizing analgesics and tricyclics antidepressants.

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• Causes of myopathy in HIV:
  • HIV itself
  • zidovudine (AZT)
  • generalized wasting syndrome
• Severe myopathy is associated with both inflammatory and noninflammatory processes.
•  Substantial muscle loss has been reported after long-term zidovudine treatment.
  • this adverse effect of zidovudine may be due to interference with mitocondrial polymerase function
  • Muscle loss due to zidovudine is reversible upon discontinuation of the drug.

• Opportunistic infections: complication of advanced HIV disease (CD4 T cells less than 200 per microliter.
• Major opportunistic infections include:
  • Pneumocystis carinii
  • Cytomegalovirus (CMV)
  • Mycobacterium avium
• About 80% of AIDS patients die as a result of an opportunistic infection.

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• Pneumocystis carinii (P. carinii): common HIV infection -declining incidence.
• P. carinii pneumonia (PCP): AIDS-defining illness in about 20% of HIV patients.
• About 50% of HIV patients will contract PCP pneumonia at least once.
• PCP pneumonia, because of HIV, is now a growing cause of community acquired pneumonia.
• Risk of PCP pneumonia increases as CD4 T cell counts decline.
• Patients with CD4 T cell accounts less than 200/microliter have a significantly higher likelihood of contracting PCP.
• With prophylaxis against Pneumocystis carinii, PCP is now occurring when the median CD4 T cell count is about 36/microliter.
• PCP definitive diagnosis requires and demonstration of trophozoite or cyst form of the organism in samples from sputum, bronchoalveolar lavage or opened lung biopsy.

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PCP Treatment

• Standard therapy: trimethoprim-sulfamethoxazole (Bactrim) [IV and oral formulation]
  • High incidence of side effects (about 50 % -- 65%) in HIV patient population.
    • rash, fever, leukopenia, thrombocytopenia, and hepatitis
    • More serious hypersensitivity reactions possible including Stevens-Johnson syndrome
  • Possibly advisable not to prescribe zidovudine or ganciclovir, because of cumulative myelotoxic effects.

• In patients unable to tolerate trimethoprim/sulfamethoxazole, pentamidine isethionate may be used (parenteral administration only)
  • Slow administration required to avoid cardiovascular adverse effects.
  •  Compared to trimethoprim/sulfamethoxazole, pentamidine is associated with more adverse side effects including:
    • Nephrotoxicity [dosage reduction necessary]
    • Pancreatitis [requires discontinuation of pentamidine]
    • hyper- or hypo-glycemia. [Probably secondary to pancreatic damage]
• Other alternatives include:
  • trimethoprim/dapsone (oral)
  • clindamycin (Cleocin)/primaquine (oral and parenteral)
  • atovaquone (oral only)
  • trimetrexate/leucovorin (oral and parenteral)
  • The combination of trimethoprim/dapsone is comparable in effectiveness to trimethoprim/sulfamethoxazole, with fewer toxicities

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Pneumocystis Prophylaxis

• Pneumocystis prophylaxis its central in management of HIV-infected patients.
• Pneumocystis prophylaxis is indicated when:
  • previous PCP infection has occurred
  • patient's CD₄ T cell level < 200 per microliter
  • presence of unexplained fever (> 100^o F)
  • history of oropharyngeal candidiasis.
• Preferred medication for prophylaxis: trimethoprim-sulfamethoxazole (Bactrim)
  •  aerosolized pentamidine (Pentam) was associated with increased jeopardy of recurrence
  • aerosolized pentamidine use is associated with increased likelihood of disseminated pneumocystosis.
  • Combination of dapsone, pyrimethamine, and leucovorin may be the alternative for patients intolerant of trimethoprim (generic) sulfamethoxazole (Gantanol); aerosolized pentamidine (Pentam) remains an option.

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Toxoplasmosis

•  Toxoplasma gondii second most common cause of secondary CNS infections in AIDS patients (about 40 percent of all CNS infections)
• Accounts for over 50% of CNS mass lesions.
• Responsible for about 3% of first seizures.
• Toxoplasmosis present is about 15% of HIV patients.
• Usually a late complication of HIV disease.
• Most common clinical presentation:
  • fever
  • headache
  • focal neurologic deficits (90% of patients)
  • Diagnosis usually based on MRI (preferred) or double-dose contrast computed tomography.
  • Definitive diagnosis: brain biopsy.
    • typically biopsy will not be performed (because of perioperative morbidity) unless patient is unresponsive to treatment. Treatment is initiated based on imaging and seropositivity.

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Toxoplasmosis Treatment

• Standard treatment: combination therapy with pyrimethamine and sulfadiazine
• Response rate: 90% -- Relapse rate within six months-about 50%.
• Therapeutic complications with Pyrimethamine (Daraprim) and sulfadiazine combination:
  • Leukopenia -- main side effect
  • Dosages of myelosuppressive antiviral agents, such as zidovudine (Retrovir, AZT, azidothymidine) or ganciclovir (DHPG, Cytovene)r, may have to be reduced.
  • Fever
  • rash
  • thrombocytopenia
  • renal failure, secondary to sulfadiazine crystalluria.
  • Side effects are common (45% -- 70%).
• Alternative therapy:
  •  Clindamycin (Cleocin) and pyrimethamine (Daraprim): almost as effective as pyrimethamine (Daraprim) and sulfadiazine.
  • Atovaquone (Mepron) and pyrimethamine (Daraprim)
  • Azithromycin (Zythromax) plus rifabutin (Mycobutin) plus pyrimethamine (Daraprim).
  • Atovaquone: broad anti-protozoal activity; effective alternative therapy for patients who have been unresponsive or who have significant adverse reactions to standard therapy.

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Toxoplasmosis Prophylaxis

•  Patients receiving and trimethoprim/sulfamethoxazole or dapsone and pyrimethamine for Pneumocystis carinii prophylaxis, also are decreased risk for toxoplasmosis.
•  Adverse effects associated with drugs used to treat toxoplasmosis are sufficiently serious to make those drugs (perhaps with the exception of atovaquone) questionable choices for prophylaxis

• Diarrhea in HIV:
  • Causative agents --
    • Cryptospiridia
    • Microsporidia
    • Isospora belli
•  Cryptospiridium:common cause of diarrhea: in HIV diarrhea may be self-limited or intermittent in early stages of disease, but may be in severe and life-threatening in advanced immunodeficiency.
  •  Approximately 1% risk of cryptosporidosis per year, if CD4 T cell counts < 300/microliter.
  • Watery stools: up to several liters per day in volume.
  • Diarrhea accompanied by crampy abdominal pain -- about one-quarter of patients experienced nausea and / or vomiting.
  • Lactose intolerance and malabsorption may accompanying Cryptospiridium GI infection.
  • Diagnosis: in -- stool examination.
  • No effective treatment known:symptomatic management only.
• Microsporidia: most common cause -- Enterocytozoon bieneusi
  • Symptoms similar to Cryptospiridium infection.
  • Extraintestinal localizations: muscle, liver, eye (by contrast to Cryptospiridium)
  • Diagnosis: definitive by electron microscopy; organism identifiable by light microscopy.
  • No effective treatment known:symptomatic management only.
• Isospora belli:coccidian parasite -- most commonly a cause of diarrhea in Carribean and African patients.
• Identical symptoms to Cryptospiridia.
• Effectively treated with trimethoprim-sulfamethoxazole (Bactrim)

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• Leading cause of death in HIV patients.
• Most common opportunistic bacterial infection (In the United States): Mycobacterium avium complex (MAC)
• Many different infections due to Mycobacterium.

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• Entry: gastrointestinal and respiratory tract.
• MAC infection:-- late complication of HIV; CD4 T cell counts < 100 per microliter.
•  With prophylaxis, CD4 T cell counts at MAC diagnosis: < 10 per microliter.
• HIV patients with MAC infection: medium survival of about 6 to 10 months. (Indicative of late stage).
• Most common clinical presentations: weight loss, night sweats, fever.
• 85% of HIV patients with MAC infection are mycobacteremic.
• Liver involvement common; abnormal chest radiographs, lymphadenopathy, abdominal pain, diarrhea
•   Pharmacological treatment of choice: clarithromycin and ethambutol.
  • a third agent may be added: rifabutin (Mycobutin), rifampin (Rimactane), clofazimine, ciprofloxacin (Cipro), or amikacin (Amikin)
• In advanced HIV infection,bacteremia and death is delayed by use of:
  • Rifabutin (Mycobutin)(see d4T cells < 75 to 100 per microliter)
  • Clarithromycin (Biaxin) or azithromycin (Zythromax) may provide better or prophylaxis in patients with CD4 T cell counts < 75 per microliter.
    • a single agent macrolide for prophylaxis may now be preferred to rifabutin.

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• About 5% of AIDS patients have active tuberculosis.
• In HIV patients with a positive purified protein derivative (PPD) skin- test, re-activation rates are about 7 to 10% per year.
• Tuberculosis results in a more rapid progression of HIV infection.
  • HIV viremia is increased during tuberculosis infection.
  • HIV viremia decreases back to baseline following successful treatment.
  • By contrast to Mycobacterium avium complex (MAC), which occurs relatively late in the course of HIV disease, tuberculosis is among the earlier signs of HIV infection.

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• Symptomatology:
  • Relatively high CD₄ T cell counts: fever, call, dyspnea on exertion, positive chest x-ray (cavitary apical disease of the upper lobes)
  •  Relatively low CD₄T cell counts: Disseminated disease -- diffuse/lower lobe, bilateral reticulonodular infiltrates, pleural effusions, hilar and/or mediastinal adenopathy. Involvement may extend to:
  • brain
  • bone
  • meninges
  • GI tract
  • lymph nodes (especially cervical)
  • in patients with low CD₄T cell counts -- 60% to 80% of patients have pulmonary disease; 30% to 40% and extrapulmonary disease.

Tuberculosis Treatment in HIV Patients

• Tuberculosis is curable in HIV patients.
• Isoniazid (INH) and rifampin (Rimactane) are first-line drugs
• MDR tuberculosis (multidrug resistance) is presently decreasing in incidence.

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• Non-mycobacterial infections are leading cause of death in HIV.
• Clinical presentations: respiratory tract infection, sepsis, gastroenteritis.
• Common bacterial infections in HIV:
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • (six fold increase in pneumococcal pneumonia incidence in HIV patients;100-fold increase in pneumococcal bacteremia) -- accordingly, HIV patients should receive pneumococcal polysaccharide vaccination.
• About one-third of HIV patients' bacteremia: Staphylococcus aureus.
• Other bacterial infections seen in HIV:
  • Salmonella
  • Shigella
  • Campylobacter
  • Bartonella
  • Treponoma pallidum (syphilis)
    • most common presentation: condyloma lata (secondary syphilis)
    • neurosyphilis

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• Candida infections: the most common fungal infections in HIV patients.
• Often occur early in HIV disease.
• May signify onset of clinical manifestation of immunodeficiency.
• Generally easy to control
• Range of infections:
  • Oral cavity (thrush): white, exudate on posterior oropharynx.
  • In late stages of HIV infection (see for T cell accounts less than 100 per microliter):
    • Candida infections: esophagus, lungs, bronchi, trachea -- -- indicative of severe immunodeficiency.
    • Esophagitis, not responsive to therapy directed at Candida,may be due to an other causes, such as, cytomegalovirus infection, HSV, Kaposi sarcoma, lymphoma

Treatment

• Oral or vaginal Candida: topical nystatin (Mycostatin) or clotrimazole (Mycelex) troches.
• In severe cases: systemic therapy-- ketoconazole (Nizoral) or fluconazole (Diflucan)
  • Fluconazole (Diflucan) may be preferable (ketoconazole (Nizoral)e may be less well absorbed in patients with high gastric pH)
• Another option for management of severe cases: IV amphotericin B (Fungizone, Amphotec), then oral fluconazole (Diflucan).

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• Leading cause of meningitis in HIV patients.
• Cryptococcus neoformans, a fungus: -- life threatening infection in 6% to 12% of AIDS patients.
• Generally occurs with advanced disease (CD4 T cell counts < 100 per microliter)
•  Cryptococcus neoformans enters the body through the respiratory tract, but the infection sites are generally the brain and meninges.[CNS infection -- 67% to 85%]
  •  Patients present with subacute meningioencephalitis
  •  Patients, in addition to meningitis, may present with cryptococcoma.
  •  Common symptoms:
    •  fever (frequency: 100%)
    •  altered mental status
    •  headache
    •  meningeal signs
  •  Pulmonary manifestation: 40% of patients with CNS infection
    •  Common symptoms:
      •  fever
      •  cough
      •  dyspnea
  • Definitive diagnosis: organism culture from spinal fluid, blood, bone marrow, sputum, or tissue

Cryptococcal Infections: Treatment

• Therapy: initiated immediately when antigen or culture tests our positive for cryptococcal infection
• Standard therapy in HIV patients:amphotericin B (Fungizone, Amphotec) in combination with flucytosine (Ancobon)..
  • Due to neutropenia, more than half of patients will not be able to receive the full course of flucytosine (Ancobon) treatment.
• Since over 50 percent of HIV patients will suffer a relapse, following amphotericin B (Fungizone, Amphotec) treatment, patients should be maintained on fluconazole (Diflucan) indefinitely.
• Fluconazole (Diflucan) is sometimes used as prophylaxis against candidal and cryptococcal infections when CD₄ T cell count < 100 per microliter.

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• Most commonly seen:in regions where Histoplasma capsulatum is endemic. (Mississippi and Ohio River Valley).
• For these geographic reasons, there are about 0. 5% of histoplasmosis-AIDS cases in the United States overall.
• Generally a late manifestation of HIV (median CD₄T cell count for patients with histoplasmosis -- 33 per microliter); occasionally, histoplasmosis is the first presenting clinical indication.
• Histoplasma capsulatum:may present initially as a pulmonary infection,disseminated disease is the most common clinical presentation in HIV.
• Clinical presentations:
  • fever
  • weight loss
  • lymphadenopathy
  • hepatosplenomegaly
  • Bone marrow involvement (33%):
    •  thrombocytopenia
    •  neutropenia
    • anemia
  • Abnormal chest x-ray (50% of patients: diffuse interstitial infiltrate or diffuse small nodules)
• Diagnosis: organism culture from blood, bone marrow, or tissue.
• Treatment: initially --amphotericin B (Fungizone, Amphotec): maintenance -- amphotericin B (Fungizone, Amphotec) or oral itraconazole (Sporanox).

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•  Significant problem throughout the course of HIV infection.
• Viral infections of special concern:
  • Cytomegalovirus (CMV)
  • Herpes simplex virus
  • Varicella zoster virus
  • Epstein-Barr virus

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•  In HIV, the clinical problem is the re-activation of latent CMV.
• Clinical presentations:
  • generally late in HIV disease (CD₄ T cell count < 50 per microliter)
  • Retinitis
    •  perhaps the most devastating manifestation (frequency:25% to 30%)
    •  progressive, painless loss of vision
    • usually bilateral; diagnosis: direct clinical assessment by an experienced ophthalmologist
    • retinal appearance:perivascular hemorrhage and exudate.
    • Necrotic inflammatory process: reversible vision loss
  • Esophagitis
    • Presentations: chest pain (substernal); odynophagia (pain on swallowing)
    • Diagnosis: endoscopy -- usually reveals distal esophageal bolster
  • Colitis
    • Frequency:5% to 10% of AIDS patients.
    • Clinical presentations:
      • diarrhea
      • abdominal pain
      • weight loss
      • anorexia
    • Diagnosis: endoscopy -- usually reveals multiple mucosal ulcerations.
      • Barium enema may be appear normal; consequently, HIV patients with CMV colitis may suffer abdominal perforation and bacteremia.
  • some other CMV manifestations in HIV patients:
    • pneumonia
    • ascending myelitis
    • subacute polyneuropathy

Cytomegalovirus Treatment

• Three major drugs for treatment of systemic CMV infection: Ganciclovir (DHPG, Cytovene), Cidofovir, Foscarnet
• Ganciclovir (DHPG, Cytovene) and cidofovir (Vistide): available as ocular implants.

• Retinitis: (photograph )
  • Initial response rates: 80% to 90% following ganciclovir or foscarnet. [Ganciclovir-easier to administer for initial therapy]
    •  Ganciclovir (DHPG, Cytovene): high incidence of bone marrow suppression -- may not be given in combination with zidovudine or trimethoprim/sulfamethoxazole.
    •   Foscarnet (Foscavir): high incidence of renal/electrolyte disorders
    •  Maintenance therapy is required following initial response -- note relapse rates are very high.
      • Oral ganciclovir is licensed for CMV prophylaxis -- oral ganciclovir delays the development of CMV disease
    • In patients without renal dysfunction, patients treated with foscarnet (Foscavir)exhibited slightly longer survival then those treated with ganciclovir (DHPG, Cytovene)r. (Perhaps because foscarnet has activity against HIV as well as CMV)
    • One common protocol involves initial treatment with ganciclovir and maintenance treatment with foscarnet
    •  Ganciclovir (DHPG, Cytovene)-resistant strains would be treated with either cidofovir or foscarnet
    •  Cidofovir (Vistide)-- less potent, however easier to administer
      • cidofovir (Vistide) side effects: leukopenia, weakness, nausea, diarrhea, decreased intraocular pressure

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• Associated with orolabial, genital, perianal lesions.
• Frequency and severity of infections increase as CD₄ T cell count decreases.
• HSV may also cause esophagitis, manifested at multiple small ulcers.
• HSV and VZV rarely cause a widespread, bilateral necrotizing retinitis: acute retinal necrosis syndrome.--characterized by kerititis, pain, iritis.

HSV Treatment

• Severe or recurrent HSV: acyclovir (Zovirax)
• Alternative: famciclovir (Famvir)
•  Valacyclovir (Valtrex), Although effective for recurrent herpes simplex in HIV, valacyclovir should be avoided because of reported fatal cases of thrombotic thrombocytopenic purpura
• Herpes strains resistant to acyclovir are increasingly common; these resistant strains are also resistant to ganciclovir -- sensitivity to foscarnet usually remains.

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• Varicella zoster virus: (chickenpox); latent in dorsal root ganglia after initial infection.
• Shingles occur or upon reactivation.
• Shingles in a patient under 50 years of age may suggest immunodeficiency, including HIV.
• Shingles is an early indication of HIV-induced immunodeficiency.
• Clinical presentation:
  • VZV infection in HIV is usually confined to the skin
  • Acute retinal necrosis syndrome: rarely seen, associated with trigeminal shingles.
•  Primary infection (not recurrent) may be fatal -- should be aggressively treated with acyclovir (Zovirax) and hyperimmuune globulin.
• If shingles are treated, lesions may resolve more quickly
  • treatment options: high-dose oral or IV acyclovir (Zovirax) or oral famciclovir (Famvir); acyclovir (Zovirax)-resistant strains-- foscarnet (Foscavir)

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• Epstein-Barr virus: a cause of infectious mononucleosis-- a common infection in HIV patients.
• May play a role in causing oral hairy leukoplakia (white lesions-- lateral aspect of the tongue and adjacent buccal mucosa --sometimes confused with candidiasis, but lesions cannot be removed by scraping).
• May be associated with lymphoma.

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• Human herpesvirus 8 (HHV-8): associated with Kaposi's sarcoma lesions and body cavity lymphoma in HIV patients -- no specific treatment
• Human herpesvirus 6:causes exanthem subitum in infants(remittant fever lasting three days, followed by crisis then a few hours later by a rash on the trunk)
• JC virus infection: human papovarvirus --causes progressive multifocal leukoencephalopathy (PML); important opportunistic pathogen in AIDS patients.
  • Demyelinating disease, beginning as subcortical white matter foci; eventually cerebral hemispheres, cerebellum, and brain stem involvement.
  • Protracted clinical course: multifocal neurological deficits:
    • ataxia, hemiparesis, visual field defects, aphasia, sensory defects.
  • Possible Treatment: intrathecal cytosine arabinoside; no consistently effective treatment presently available (1997)
• Human Papilloma virus: common in HIV patients (about two times more common than in general population)
  • Virus is associated with epidural dysplasia.
• Hepatitis viruses:
  • Nearly all of HIV-infected individuals show evidence of hepatitis B infection.
  • Co-infection with hepatitis C and/or D is common;
  • presence of HIV infection may slightly worsen hepatic disease;
  • Patients with HIV infection may respond more poorly to IFN-alpha therapy for hepatitis B then non-HIV patients.

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• Significant contributors to morbidity and mortality in HIV.
  • Kaposi sarcoma
  • Lymphoma
  • Intraepithelial dysplasia of the cervix and anus

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• Multicentric neoplasm: multiple vascular nodules -- skin, mucous membranes, viscera.
• Minor to extensive involvement.
• A sexually transmitted to factor appears to play a significant role in Kaposi sarcoma development. (HHV 8 maybe this viral cofactor)
• Almost exclusively associated with homosexual men. With the decline of HIV infection rates in this population, the rate of appearance of Kaposi sarcoma has also declined.
• Can be an early manifestation of HIV infection (normal CD₄ T cell counts)
• With better management of opportunistic infections, Kaposi's sarcoma is now appearing as a late manifestation of HIV infection
• ay result from cytokine dysregulation.
• Characteristics of tumor.
  •  vascular in nature
  •  color: reddish to purple to brown (bruise-like)
  •  size: few mm -- several cm
• Tissues affected:
  • Skin
  • Lymph nodes
  • Gastrointestinal tract
  • Lung
  • Spleen

Kaposi's Sarcoma: Treatment

• Since less than 10% of AIDS patients with Kaposi sarcoma die of malignancy -- death from opportunistic infection is much more common, treatment that suppresses immune function should be avoided.
  • Treatment is palliative, not associated with enhanced survival.
  • Circumstances for Treatment:
    • Cosmetic problems; significant discomfort --
      •  localized irradiation (HIV patients are especially sensitive to radiation therapy side effects)
      •  intralesional vinblastine
      • cryotherapy (if possible)
    • Large number of lesions:
      • single agent chemotherapy
        • etoposide (VP-16,VePe-sid)
        • vinblastine (Velban)
        • oxorubicin (Adriamycin)
        • bleomycin (Blenoxane)
        • IFN-alpha 
      • The most important predictor of therapeutic response to single agent chemotherapy is CD₄ T cell count.
    • In life-threatening cases, combination therapy is indicated: drug combinations include --
      • low dose doxorubicin (Adriamycin), bleomycin (Blenoxane), and vinblastine (Velban).

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•  About 6% of HIV patients develop lymphoma (approximately and 120-fold increase over the incidence in the general population)
• Late manifestation of HIV-- CD₄ T cell count < 200 per microliter
• As HIV patients live longer because of improved antiretroviral treatment, better management and prophylaxis of opportunistic infections, lymphomas may appear more frequently.
• Three major lymphoma types occur in HIV infected patients:
  • grade III or IV immunoblastic lymphoma
  • Burkitt's lymphoma
  • primary CNS lymphoma
• Most (90%) are B-cell phenotype; about half contain Epstein-Barr viral DNAImmunoblastic lymphoma
  • Accounts for about 60% of lymphoma seen in HIV
  • more common in older patients
  •  generally high-grade
• Burkitt's lymphoma (small noncleaved cell lymphoma)
  • Accounts for about 20% of lymphoma seen in HIV.
  • Age-group: 10 to 19 years of age.
  • Frequency in HIV population: about 1000-fold higher than in the general population.
  • About 50% of HIV-Burkitt's lymphoma contain Epstein-Barr viral genome (and African Burkitt's lymphoma -- 97% contain Epstein-Barr)
• Primary CNS lymphoma
  • Accounts for about 20 percent of lymphoma in HIV.
  • Most primary CNS lymphomas are positive for Epstein-Barr.
  • CNS lymphoma in HIV patients-- associated with advanced disease (CD4 T cell count less than 40 per microliter)
  • Focal neurological deficits including headaches, seizures, cranial nerve involvement.
• Clinical presentations: varied
  • focal seizures -- rapidly growing mass lesions
  • At least 80% of HIV lymphoma patients present with:
    • extranodal disease (including gastrointestinal sites, 25%) and
    • night sweats and than in
    • fever than
    • weight loss

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HIV-Lymphoma Treatment

•  Low response rates and high incidence of opportunistic infections were associated with standard intensive therapeutic approaches -- now largely abandoned
  • Median survival for patients treated with intensive protocols: 4-6 months. (Note these patients usually have relatively advanced HIV disease with low CD₄ T cell counts)
• Low-dose protocols are presently being evaluated.
• Primary CNS lymphoma:
  • Nearly always unsuccessful-- median survival two to four months.
  • Palliative approaches:
    • radiation
    • glucocorticoids

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• Complication of HIV infection
• Human papilloma virus-associated condition -- intraepithelial neoplasia -- invasive cancer.
• As HIV patients live longer, and increased incidence of these diseases may be expected.
• All HIV patients: periodic pelvic/rectal examination to detect cellular dysplasia.

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• Withhold antiretroviral treatment until CD₄ T cell counts < 500 per microliter. This approach should only be followed if there is good reason to believe that the patient will not be compliant with the multidrug regimen. Current HIV treatment guidelines suggest that treatments which will reduce viral loads should be offered to patients as early as possible {within the above constraint. However, long-term serious side effects associated with current highly active antiretroviral combination therapy has resulted in reevaluation of the optimal treatment approach. The reader should consult the most recent CDC guidelines concerning HIV therapeutic options.
• Initiate treatment with:
  • 2 nucleosides plus 1 protease inhibitor
  • 2 nucleosides plus 1 non-nucleoside
  • 2 nucleosides plus ritonavir (Norvir) plus another protease inhibitor
• Chosen approach would be retained until disease progression, defined by CD₄ T cell counts below 200 per microliter.
• New treatment protocol implemented at this time, probably including one or two new nucleosides plus a protease inhibitor.

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• Immune-based treatment
  • IFN-alpha
  • bone marrow transplantation with lymphocytes transfer
  • thymic implantation
  • active immunotherapy: e.g. envelope vaccines
  • passive immunotherapy: inactivated anti-HIV and antisera, HIV-specific monoclonal antibodies, interleukin2 administration.

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• Prevention of secondary infection: important in survival in quality of life for HIV patients
• Pneumocystis carinii infection: prophylaxis if CD₄T cell count falls below 200 per microliter or CD4 percentage decreases below 15 percent.
  • PCP prophylaxis: trimethoprim-sulfamethoxazole (Bactrim).(also provides protection against toxoplasmosis and certain bacterial infections)
  • Alternative PCP prophylaxis: dapsone/p pyrimethamine (Daraprim), clindamycin (Cleocin)/ primaquine
  • in patients intolerant of the above protocols, aerosolized pentamidine (Pentam)
• Mycobacterium avium complex (MAC): extremely common infection; typically seen when CD₄ T cell counts < 100 per microliter:
  • MAC prophylaxis: rifabutin (Mycobutin)
  • Alternative MAC prophylaxis: clarithromycin (Biaxin), azithromycin (Zythromax)(probably better than rifabutin (Mycobutin))

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Indication for Antiviral Treatment

• Clinical category: -- Acute HIV or < 6 months after seroconversion
  • All CD₄T cell counts and HIV RNA levels
  • Recommendation: Treat
    • Highly active anti-retroviral treatment (HAART) in which three or four agents are combined use the standard of care for managing human immunodeficiency virus infection.
    • These protocols involving three or four drugs, using combination, can:
      •  decrease viral replication
      •  improve immunologic status and
      •  prolong life
        • Basis of treatment:
          • suppression of initial burst of viral replication, decreasing the magnitude of virus dissemination through the body
          • decrease the severity of acute disease
          • potentially alter the initial viral"set-point",which may affect the rate of disease progression
          • possible reduction in rate of viral mutation due to suppression of viral replication.
• Clinical category:-- Symptomatic (thrush, unexplained fever,AIDS)
  • All CD₄ T cell counts and HIV RNA levels
  • Recommendation: treat
• Clinical category: -- Asymptomatic:
  • CD₄ T cell count < 500 per microliter or HIV RNA >10,000 (bDNA) or > 20,000 (RT -- PCR
  • Recommendation: Treat (consideration given based on prognosis for disease-free survival time and willingness of patient to accept therapy)
• Clinical category: -- Asymptomatic:
  • CD₄CD₄ T cell counts > 500 per microliter and HIV RNA < 10,000 (bDNA) or less than 20,000 (RT-PCR)
  • Recommendation: Treat:
    • Rationale: Reduction of patient viral load, improved immunological status, prolongation of life
    • Effective therapy requires rigorous compliance in taking medication.

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Treatment Protocol (January, 2000)--check CDC for more current information

• Drugs of choice for Adult HIV infection:

• Alternatives:
  • One protease inhibitor plus one nucleoside plus one non-nucleoside
  • Two protease inhibitors (each low-dose) plus 1 nucleoside plus 1 nucleoside
  • Abacavir (Ziagen) plus two other nucleosides
  • Two protease inhibitors (each full dose)
• Not generally recommended: Clinical benefits demonstrated by the initial viral suppression not sustainable by most patients
  • Two nucleoside reverse transcriptase inhibitors
  • Saquinavir (Invirase) plus two nucleoside reverse transcriptase inhibitors
•  Not recommended: Evidence against use, virologically undesirable or exhibiting overlapping toxicities
  • All monotherapies, d4T plus AZT, ddC plus ddI, ddC plus d4T, ddC plus 3TC.

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• "Drugs for HIV Infection", The Medical Letter, volume 42 (issue 1069), Jan. 10, 2000, Published by The Medical Letter, Inc., 1000 Main Street, New Rochelle, New York, 10801